In 1989, we began a study to determine whether or not adult-onset DR could slow the aging process in a primate species. This work was originally supported by an R01, and since 1994 has been funded by the National Institute on Aging (NIA) through the Program Project Grant (P01) mechanism. In January 2010 we submitted an application to NIA for continued funding of this project through the P01 mechanism that reviewed very well (18th percentile). Unfortunately, due to the current funding climate, it is unlikely that this application will be funded. We were therefore strongly encouraged by our NIA program officer to submit this R01 to continue the key aspects of this long-term study. Accordingly, we request support to span 2011 - 2016 (when the study would be in its 27th year) to continue this unique and exciting endeavor to its natural conclusion of maximum lifespan. Through our previous 20+ years of research we have demonstrated the suitability of the rhesus monkey aging model and, quite recently, the efficacy of DR in slowing major features of biological aging. These include sarcopenia as well as delaying morbidity, brain atrophy and mortality. Importantly, these latter studies are not yet complete as 30 of the original 76 monkeys (39%) are alive. Thus, the goal of this application is to get five years closer to having data for all animals on healthspan and lifespan. There are two Specific Aims: Specific Aim 1: To determine DR's influence on the rate of aging in a primate species by evaluating indicators of biological age, healthspan and disease patterns. We are testing a moderate adult-onset DR (30% calorie reduction) on female and male rhesus monkeys and have made significant progress on this Aim;however, fully achieving it will require several more years as the study's oldest monkeys (~30 years) are only now becoming quite old (average rhesus lifespan is ~27 years, maximum lifespan is ~40 years). Over the next 5 years, these animals will be of an age at which increases of age-related morbidity are expressed. Specific Aim 2: To determine DR's influence on maximal lifespan in a primate species. While we have made significant progress in determining DR's influence on the rate of aging we are not yet able to determine the ability of DR to alter maximal lifespan in a primate species. Over the next 5 years, the animals will be rapidly approaching an age at which will be able to determine whether DR increases maximal lifespan. Gerontologists have eagerly awaited these data for decades. Based on the media response to our recent Science publication our study is of broad general interest. A major clinical implication is that DR represents a metabolic state opposite that of type 2 diabetes which, to date, has been completely prevented by DR in our monkeys. This observation has obvious public health implications while an obesity/diabetes epidemic is prominent. These data may have a very significant public health impact by demonstrating the health and longevity benefits triggered by DR in primates and should stimulate efforts to mimic these effects by drug or dietary interventions. PUBLIC HEALTH RELEVANCE: Our rapidly growing aging population deems interventions that delay or prevent age-associated disease to be of huge public health significance. DR (less calories eaten but without a shortage of essential nutrients) is the most potent dietary intervention that opposes a broad array of age-associated health problems in laboratory rodents. This 21-year-long project has recently discovered similar beneficial effects in monkeys and seeks both to extend these findings and to learn how DR is able to increase the healthy lifespan. !